PROJECT SUMMARY Long-term persistence in an infected host is an essential step in the life cycle of many viruses. The human adenoviruses (HAdVs) are persistent pathogens, remaining in an infected host for an extended period of time following acute infection. HAdV persists in lymphocytes, but the consequences of persistence on lymphocyte function are unknown. HAdV persistence is linked to an increasing variety of chronic diseases, including dilated cardiomyopathy, asthma, and chronic obstructive pulmonary disease. Despite the substantial clinical impact of HAdV infections, effective therapies are not available to prevent or treat acute or persistent HAdV infection. The long-term goal of our research is to increase fundamental knowledge about adenovirus persistence and the impact of persistence on disease. The objective of this application is to characterize adenovirus persistence in a tractable animal model, identifying specific types of T cells that harbor persistent virus and defining the effects of virus persistence on T cell function. The strict species-specificity of the adenoviruses limits studies of HAdV pathogenesis. We have established a mouse model using mouse adenovirus type 1 (MAV-1) that allows the study of the pathogenesis of an adenovirus in its natural host. We have used MAV-1 to define important host factors that contribute to the pathogenesis of myocarditis and respiratory infection. Our published and preliminary data indicate that MAV-1 persists in T cells over extended periods of time in an infected mouse. In addition, we detect long-term upregulation of IFN-? expression that correspond to histone modifications of the IFN-? locus in infected mice. This proposal seeks to test the overall hypothesis that MAV-1 persistence in T cells induces long-term changes that alter T cell function. Aim 1 will identify specific tissue and cellular reservoirs of persistent virus and determine whether interferons promote virus persistence. Aim 2 will define effects of virus persistence on T cell function and determine the extent to which those effects are due to histone modifications that regulate IFN-? expression. The results of our proposed work will provide detailed information regarding mechanisms that regulate adenovirus persistence and effects of adenovirus persistence on immune function. Results of our work will expand the understanding of this key aspect of adenovirus biology and may identify novel targets for therapies that will improve outcomes for patients with diseases caused by HAdV infection.